Compartmentalization of the host microbiome: how tumor microbiota shapes checkpoint immunotherapy outcome and offers therapeutic prospects

Abstract

The host microbiome is polymorphic, compartmentalized, and composed of distinctive tissue microbiomes. While research in the field of cancer immunotherapy has provided an improved understanding of the interaction with the gastrointestinal microbiome, the significance of the tumor-associated microbiome has only recently been grasped. This article provides a state-of-the-art review about the tumor-associated microbiome and sheds light on how local tumor microbiota shapes anticancer immunity and influences checkpoint immunotherapy outcome. The direct route of interaction between cancer cells, immune cells, and microbiota in the tumor microenvironment is emphasized and advocates a focus on the tumor-associated microbiome in addition to the spatially separated gut compartment. Since the mechanisms underlying checkpoint immunotherapy modulation by tumor-associated microbiota remain largely elusive, future research should dissect the pathways involved and outline strategies to therapeutically modulate microbes and their products within the tumor microenvironment. A more detailed knowledge about the mechanisms governing the composition and functional quality of the tumor microbiome will improve cancer immunotherapy and advance precision medicine for solid tumors.

Keywords: Immunotherapy.

Figure 1

Compartmentalization of the microbiome in cancer. Distinctive microbiomes are found in various anatomical compartments of patients with cancer, here categorized as GI microbiome, tumor microbiome and distinctive tissue microbiomes. These microbiomes are physically separated yet functionally interact with each other. The tumor microbiota plays an outstanding role as interactions with cancer cells and tumor-infiltrating immune cells may be more direct as compared with the GI microbiome and other tissue microbiomes. Specifically, interactions with tumor and immune cells can occur via the systemic route (eg, circulation) in all three scenarios, while local (‘physical’) interactions are exclusive to the tumor microbiome. This suggests distinct effects of different microbial habitats on cancer immunotherapy efficacy. Figure is created with BioRender.com. GI, gastrointestinal.

Figure 2

Systemic and local effects of microbes on tumorigenesis and immune cells. Shown are principal mechanisms by which microbiota may influence tumorigenesis and local immune cells that take effect on cancer immunotherapy efficacy. Microbiota can have direct effects on the immunotherapy target cells (ie, cancer cells) or regulate the amplitude and quality of the anticancer immune response both on and off treatment: (1) Microbial metabolites (of GI microbiota, likely also of local microbiota) may promote T cell activation and differentiation, resulting in the accumulation of both proinflammatory (eg, effector T cells) and immunosuppressive (eg, T regulatory cells) immune cell populations in the TME. (2) MHC class II-expressing cells (eg, DCs) presenting microbial antigens may activate T cells in tumor-draining lymph nodes. Molecular mimicry of tumor antigens by microbial peptides would result in tumor-directed T cell activity, thereby influencing cancer immunotherapy efficacy. (3) Bacterial molecules (pathogen-associated molecular patterns) such as LPS may bind TLRs (eg, TLR4) on TAMs/TANs or directly activate tumor-associated NK cells (eg, via IFNγ signaling). This may activate downstream pro-inflammatory pathways and/or promote tumor cell death. (4) Genotoxic microbial products can induce DNA damage in cancer cells to reshape the tumor genome and promote cancer cell proliferation. Examples include colibactin and CDT that both induce transient cell cycle arrest (promoting the occurrence of genomic errors during the repair process) and double-strand breaks leading to chromosomal instabilityas well as the novel genotoxin ushA (acting via DNA digestion) and ROS that directly damage cancer cells and/or induce epigenetic changes via ERK-MAPK signaling. Figure is created with BioRender.com. (IMPORTANT: move this citation to the sentence before right after "ERK-MAPK signaling".) APC, antigen-presenting cell; CDT, cytolethal distending toxin; DC, dendritic cell; LPS, lipopolysaccharide, NK, natural killer (cell); ROS, reactive oxygen species; SCFA, short-chain fatty acid; TLR, Toll-like receptor; TAM, tumor-associated macrophage; TAN, tumor-associated neutrophil; TMAO, trimethylamine N-oxide; TME, tumor microenvironment.

Figure 3

Concepts for microbiome-centered interventions. Specific microbial compartments may be amenable for therapeutic intervention to resensitize to ICI treatment. Targeted modulation of specific microbiomes may be achieved based on different conceptual approaches. Supplementing particular microbial species (eg, Bifidobacterium) using different routes of administration could modulate the tumor microbiome, the GI microbiome, and the lung microbiome, respectively, to increase the diversity and/or make the functional composition more beneficial. On the other hand, the use of narrow-spectrum antibiotics against harmful bacteria or FMT from ICI-responding patients could restore ICI efficacy in otherwise non-responding/refractory patients. Personalized vaccination against tumor-associated antigens from intracellular bacteria or viruses represents another strategy by which microbial species might be harnessed for ICI-resensitizing intervention. Finally, adopting specific dietary behaviors such as high-fiber- or fasting-mimicking diet may also facilitate ICI performance by inducing favorable immunological changes in the TME. Figure is created with BioRender.com. FMT, fecal microbiota transplantation; GI, gastrointestinal; ICI, immune checkpoint inhibitor; TME, tumor microenvironment.